N(14)-substituted evodiamine derivatives as dual topoisomerase 1/tubulin-Inhibiting anti-gastrointestinal tumor agents

Jiedan Deng; Lin Long; Xue Peng; Weifan Jiang; Ying Peng; Xi Zhang; Yuting Zhao; Ying Tian; Zhen Wang; Linsheng Zhuo

doi:10.1016/j.ejmech.2023.115366

N(14)-substituted evodiamine derivatives as dual topoisomerase 1/tubulin-Inhibiting anti-gastrointestinal tumor agents

Eur J Med Chem. 2023 Jul 5:255:115366. doi: 10.1016/j.ejmech.2023.115366. Epub 2023 Apr 20.

Authors

Jiedan Deng¹, Lin Long², Xue Peng², Weifan Jiang², Ying Peng³, Xi Zhang³, Yuting Zhao⁴, Ying Tian⁴, Zhen Wang⁵, Linsheng Zhuo⁶

Affiliations

¹ School of Pharmacy, Lanzhou University, Lanzhou, 730000, China.
² School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
³ Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
⁴ The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
⁵ School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: zhenw@lzu.edu.cn.
⁶ School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Postdoctoral Station for Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: lszhuo@usc.edu.cn.

PMID: 37099835
DOI: 10.1016/j.ejmech.2023.115366

Abstract

Gastrointestinal tumor is an important factor threatening human health. Natural product-based drug discovery is a popular paradigm for expanding the chemical space and identifying new molecular entities that ameliorate human disease. Evodiamine-inspired medicinal chemistry presents therapeutic potential for treating tumors in different tissues via multi-target inhibition. Here, by focusing on the discovery of anti-gastrointestinal tumor drugs, a series of N(14) alkyl-substituted evodiamine derivatives were designed and synthesized. The structure-activity relationship studies culminated in the identification of the N(14)-propyl-substituted evodiamine analog 6b, which showed low nanomolar inhibitory activity against MGC-803 (IC₅₀ = 0.09 μM) and RKO (IC₅₀ = 0.2 μM) cell lines. Moreover, compound 6b was effective in inducing apoptosis, arresting the cell cycle in the G2/M phase, and inhibiting migration and invasion of MGC-803 and RKO cell lines in a dose-dependent manner in vitro. Further antitumor mechanism studies revealed that compound 6b significantly inhibited topoisomerase 1 (inhibition rate of 58.3% at 50 μM) and tubulin polymerization (IC₅₀ = 5.69 μM). Overall, compound 6b represents a promising dual topoisomerase 1/tubulin-targeting lead structure for the treatment of gastrointestinal tumor.

Keywords: Anti-Tumor; Evodiamine derivatives; Top 1/ tubulin inhibitor.

MeSH terms

Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Apoptosis
Cell Line, Tumor
Cell Proliferation
Drug Screening Assays, Antitumor
Humans
Polymerization
Structure-Activity Relationship
Tubulin Modulators / pharmacology
Tubulin* / metabolism

Substances

Tubulin
Antineoplastic Agents
Tubulin Modulators